Leflunomide Derivative FK778 Inhibits Production of Antibodies in an Experimental Model of Alloreactive T-B Cell Interaction

Abstract

Objectives: The contribution of humoral immune response in allograft and xenograft rejection has been clearly demonstrated in recent years. For this reason, inhibition of alloantibody production has become essential in managing transplanted patients. Here, we assessed the effects of the leflunomide derivative FK778 (FK778) in the control of antibody production resulting from semi­allogeneic cognate T-B–cell interactions.

Materials and Methods: BALB/c mice were tolerized at birth with semiallogeneic spleen cells from (BALB/c × C57BL/6) F1 mice, with or without overexpression of human bcl-2 transgene in B cells. These tolerized mice were treated with different dosages of FK778, either from birth, or from the third week of age, when autoantibody production was detected. The production of autoantibodies, used as markers of semiallogeneic cognate T-B–cell interactions, was evaluated at different time points during drug administration or after the interruption of treatment.

Results: FK778 treatment started at birth inhibited the production of semiallogeneic-driven antibodies in a dose-dependent manner. In addition, FK778 also reduced the levels of preformed circulating autoantibodies in adult mice, although the dosage required was 4 times higher than that used in neonates. However, the levels of IgG antibodies in these tolerized mice increased after FK778 withdrawal, indicating that FK778 failed to induce tolerance to semiallogeneic host CD4+ Th2 and/or donor B cells.

Conclusions: Our results demonstrate the efficacy of FK778 in the control of antibody production resulting from semiallogeneic cognate T-B–cell interactions.